OP0201 INTRA-ARTICULAR INJECTIONS OF TWO LIPOSOMAL ADENOSINE FORMULATIONS PROVIDE SIGNIFICANT PAIN RELIEF AND GAIN IN FUNCTION, IMPROVE COMFORTABLE RANGE OF MOTION AND SLOWED RADIOLOGIC PROGRESSION IN A PRECLINICAL CANINE MODEL OF OSTEOARTHRITIS
Authors: D. LI, B. N. Cronstein, J. Cook, C. Bozynski, S. Angle
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoarthritis (OA) affects 10% of global population and its effective non-surgical treatments represent significant unmet need. There has been a rapid escalation in the annual number of arthroplasties, placing a significant burden on patients and healthcare systems. We previously demonstrated that adenosine and its A2A receptor play critical roles in maintaining joint homeostasis. Adenosine treatment prevents structural progression and preserves articular cartilage in rodent models of OA. <h3>Objectives</h3> To test the new, more stable and long-lasting formulations of liposomal adenosine in the treatment of post-traumatic OA in a preclinical canine model. <h3>Methods</h3> OA was induced by arthroscopic medial meniscus release (MR) in 21 purpose-bred hounds ([10M, 11F]). Evidence of OA was documented at two months after MR (pre-Tx). Knees were injected with 3mL of RgnA09M, RgnA09N (3 mg/ml Adenosine; N=7 each) or saline (9 mg/ml NaCl; N=7) for a total of 3 intra-articular (IA) injections each carried out one month apart. RgnA09M and RgnA09N comprised identical lipid composition but varied in particle size and liposome lamellarity. Blinded assessments for knee pain, function and effusion were performed using validated visual analogue scale (VAS) scoring by a board-certified veterinary surgeon. Comfortable range of motion (CROM) was measured using a standard goniometer and radiographic assessments of knee joints were also performed. Results presented are before surgical induction of OA (pre-MR), at pre-Tx, at 4 months (post-Tx) and the time of humane euthanasia (6 months post-Tx) for histology and histopathology. Blood for biomarkers and synovial fluid were collected at same time points. MRIs were used to evaluate cartilage structure and integrity at pre-Tx and 6 months post-Tx. Wilcoxon matched pair signed rank test was used for statistical analyses. <h3>Results</h3> There was demonstrable symptomatic knee OA at pre-Tx with a 26.3% loss in function, increased joint pain score (2.0±0.9 vs 0 at pre-MR), 10% loss of CROM, development of radiographic OA (1.2±0.5 vs. 0 at pre-MR), observable OA on MRI (3.9±0.9 vs. 0 at pre-MR) and joint effusion (2.3±0.9 vs. 0 at pre-MR). Saline treatment provided no benefits. The IA administration of RgnA09M, led to a steady decrease in pain by 65.0% and 74.3%, at 4mo and 6mo post-Tx respectively, with a corresponding 30.9% and 61.8% gain in function. In comparison, the injection of RgnA09N led to decrease in pain by 80.9% at 4mo but a loss of effect to 74.7 % at 6mo post-Tx. A corresponding trend was observed in the gain of function, with an overall gain of 39.7% at 6mo post-Tx (<b>Figures 1A</b> and <b>1B</b>). Moreover, injections with RgnA09M, improved CROM to near-normal values at 6mo, while RgnA09N significantly improved it at 4mo <b>(Figure 1C</b>). Compared to saline, both RgnA09M and RgnA09N improved radiographic markers by up to 42.6% at 6mo post-Tx <b>(Figure 1D</b>). In saline-treated dogs there was an improvement in the size of effusions initially, but a loss in benefit as time progressed. In contrary, the magnitude of the change was much greater in those treated with both formulations, and it continued to improve over time <b>(Figure 1E</b>). Finally, at 6mo post-Tx, MRIs showed significant slowing in the progression of OA with RgnA09M by 55.3% and with RgnA09N by 42.8% (<b>Figure 1F</b>). Histology and biomarker results are pending. <h3>Conclusion</h3> Three IA injections of RgnA09M and RgnA09N were associated with improved symptomatic knee OA including gain in function and decrease in pain and OA progression compared with saline. The persistent improvement lasted 6 months, indicating symptomatic and mechanistic benefits of the treatment. Moreover, liposomal adenosine injections slowed the progression of OA as observed on radiographs and MRIs. These findings provide the first evidence that IA injection of liposomal adenosine improves pain relief, gain in function, CROM, and prevents radiologic progression in a large animal model of post-traumatic OA. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Ding Li Shareholder of: Regenosine, Inc., Employee of: Regenosine, Inc., Bruce N. Cronstein Shareholder of: Regenosine, Inc., Grant/research support from: Regenosine, Inc, James Cook Paid instructor for: Journal of Knee Surgery. Midwest Transplant Network. Musculoskeletal Transplant Foundation., Consultant of: Arthrex, Inc. Trupanion., Grant/research support from: AO Trauma. Arthrex, Inc. Collagen Matrix Inc. DePuy. Musculoskeletal Transplant Foundation. Purina. Regenosine, Inc. SITES Medical. Thieme., Chantelle Bozynski: None declared, Siddhesh Angle Shareholder of: Regenosine, Inc., Grant/research support from: Vetosine, Employee of: Regenosine, Inc. Bone Biologics.